Reversal of Baldness in Men and Women through Cannabinoid Receptor Activation

ABSTRACT

This invention reverses male pattern baldness by shocking dormant hair follicles out of their androgen induced hibernation phase back to the active hair-growing anagenic phase. The invention integrates two functions: 1) It blocks synthesis of compounds holding the follicles in the telogenic/hibernating phase and 2) It stimulates synthesis of compounds animating the hair-growing/anagenic phase in the follicular activity cycle. One preferred embodiment comprises an enzyme inhibitor blocking the conversion of testosterone to dihydrotestosterone (DHT), a flavonoid simultaneously increasing synthesis of prostaglandins alternative to prostaglandin D 2 , and a selected cannabinoid compound stimulating restore the hair follicle to its normal growth cycle. This novel trimodal therapy restores the hair follicles to their normal cycling processes and maintains these restorative properties so long as this rebalance in maintained.

Male pattern baldness, also known as androgenetic alopecia, is thecommon type of hair loss that develops in most men. Hair loss becomesnoticeable generally between 25 and 50 years of age. The pace of hairloss differs greatly with progression to complete baldness in some scalpareas occurring over a range of about 5 to about 35 years from the startof hair loss.

This invention reverses the male pattern baldness process by shockingdormant hair follicles out of their androgen induced hibernation phaseto restore the normal cycling pattern and thereby re-initiate the activehair-growing anagenic phase. The invention integrates two majorfunctions: 1) It removes arresting influences that induce and maintainthe telogenic or resting phase of the follicular cycle, and 2) Itstimulates synthesis of compounds to refocus activity back to thehair-growing/anagenic phase of the cycle. One preferred embodimentcomprises an enzyme inhibitor blocking the conversion of testosterone todihydrotestosterone (DHT), a flavonoid simultaneously increasingsynthesis of prostaglandins alternative to prostaglandin D₂, and aselected cannabinoid compound stimulating restore the hair follicle toits normal growth cycle. This novel trimodal therapy restores the hairfollicles to their normal cycling processes and maintains theserestorative properties so long as this rebalance in maintained.

Hair grows out of hair follicles (HF)s, tiny factories in the epitheliumjust under the skin surface. A follicle grows a single hair for about30-40 months on average, with a range of about 24 to about 70 monthsstill considered in the normal range. The follicle then terminatesgrowth of that hair strand letting it naturally fall out as the folliclebegins growing a new strand. This cycle of hair growth, shedding and newgrowth essentially determines the maximum length of a person's hair. Inthe balding process regional HFs of the scalp gradually decrease theirsize; the smaller follicle produces thinner hair strands; the diminishedfollicles shorten the time length for each strand to grow; maximumlength decreases—eventually to a point where the stub of hair fails tobreach the skin's outer surface.

The normal hair growth cycle comprises three phases: anagen, catagen,and telogen. The first growth phase, anagen, or hair growth phase,involves hair strand production over a period between two to six years.Then the anagen phase progresses to the catagen phase, a seven tofifteen day transition phase where strand growth ceases and the hair isreleased. This is followed by the telogen phase, a one to two monthrestoration/resting phase, before the anagen phase recommences. As theandrogenic alopecia progresses the anagen growth phase diminishes inlength as the telogen resting phase gains prominence.

Androgenetic alopecia has an androgenic etiology relating todihydrotestosterone (DHT). DHT is the most abundant androgen in the skinand is made from testosterone by the 5-α reductase enzyme. Theandrogenic effect on hair is extremely site specific: hair on the chest,the pubic area, and lower face, e.g., beard area, is positivelysupported by the presence of androgens to grow thick, pigmented hair.Just a little higher on the body, HFs located on the scalp of the headrespond to DHT (and similar androgens) by shrinking and making onlynonpigmented vellus hairs.

According to the website:https://www.wikihow.com/Treat-Male-Pattern-Hair-Loss.

-   -   a) Male pattern baldness is caused by genetic predisposition and        the main androgen believed to be associated with baldness is        dihydrotestosterone (DHT).    -   b) Increased level of DHT in HFs is believed to shorten the        hair's growth cycle and delay growth of new hair.    -   c) Over time, the HFs stop growing new hair; however, the        follicles remain alive, suggesting that they may still be able        to grow new hair.

Baldness, particularly male pattern baldness, obviously has anunderlying trait associated with male development. The androgenichormone system comprises a class of steroid hormones whose increasedconcentration in males interacts with one or more of the androgenicreceptors predominant in males. The androgens are steroid hormonesprimarily produced in and then secreted by the male testes. A secondarysource of many androgens is the adrenal gland. Androgens are criticalsteroid hormones that regulate male sexual development anddifferentiation, including the formation of the reproductive system andmaintenance of its function. Androgens are also involved in muscledevelopment and psychosexual behavior. The major male androgen istestosterone. Testosterone derivatives, dihydrotestosterone (aka5α-dihydrotestosterone) (DHT) and androstenedione are instrumental inmale development. E.g., in utero, DHT directs differentiation of penis,scrotum and prostate. In later life, DHT contributes to balding,prostate growth, and sebaceous gland activity. DHT has a greateraffinity for androgen receptors than testosterone. DHT is synthesizedfrom testosterone by the enzyme 5α-reductase. DHT acts as the primaryandrogen in the genitals, prostate gland, seminal vesicles, skin, andHFs. 5α-Reductase inhibitors including, but not limited to: finasterideand dutasteride, inhibit 5α-reductase type 2 by direct binding and atmaximum may decrease circulating DHT levels by 65 to 98%.

The present invention provides therapeutic products that arrest orreverse male pattern baldness, that restore hair growth to alopecicareas and/or that rebalance the growth and resting phases of hairfollicle cycling. Product formats are not restricted and may be selectedfrom any application methods acceptable to the user. For example, thetherapeutic product may appear in a delivery format including, but notlimited to: a liquid, a topical gel, mist, cream, low viscosity liquid,ointment, spray, dermal patch, shampoo, conditioner, etc. Followinginitial follicularly targeted microinjection, additional therapeutictreatments may be delivered by one or more topical treatments such asthe creams or shampoo format. The additional therapeutic(s) follow theawakened ascending hair tracks to supplement and maintain directedstimulation. Supplements can be provided according to a preselectedschedule and or in coordination with regular activity, such as a dailyshower, a gym work out, a spa visit, etc., interspersed by one or moredays, weeks, fortnights, etc. Microinjection is possible as discussedbetween the professional and the recipient. An initial flurry oftreatments, e.g., weekly, may be tapered to bi-weekly, monthly,quarterly, etc., as decided by those involved.

The “arrest” process may commence at the earliest suspicion or detectionof initiation of the male pattern baldness process, may commence basedon family history, may commence based on racially or ethnicallyassociated norms, may commence based on societal average, may commencebased on suggestion, of friend family, co-worker etc., may commence uponcompleting a program, moving, starting new employment, etc., or maycommence simply when the recipient desires or requests such action.

An especially robust delivery format comprises a wearable devicesituated upon the scalp. The device may include one or more features foranalyzing scalp condition(s) and/or delivering stimulation to theunderlying scalp. The analysis may, for example, determine the hairfollicle density, the hair follicle activity state, the diameter and/orlocation of one or more hair shafts, nutritional indicators, etc.Stimulation may be mechanical, for example, a comforting or calmingmassage, and may be as intensive as featuring microinjectors to delivertherapeutic product to specific areas determined in advance orappropriately determined by the immediate analysis.

Two pharmaceuticals are FDA approved for androgenetic alopeciaindications, minoxidil [hypertensive treatment] and finasteride [5-αreductase type 2 inhibitor]. Another compound, dutasteride, withstronger inhibitory efficacy than finasteride has undergone preliminarytrials, but development has terminated in the US. Finasteride is a 5α-reductase inhibitor available by prescription only. DHT is aderivative or enzymatic progeny of testosterone that appears to increasecatagenic phase time at the expense of the anagenic. The 5-α-reductaseconverts testosterone to DHT which has stronger activity against hairgrowth than parent hormone molecule. DHT acts to shrink HFs, and whenDHT is adequately suppressed, HFs should continue to thrive. DHT effectmay be blocked or circumvented by depleting PGD₂.

Finasteride slows hair loss as long as you take it. However, as soon asyou discontinue therapy, hair loss typically returns within a year. Sideeffects associated with finasteride include chills; cold sweats;confusion; dizziness; hives; swelling in the legs, arms and face;tingling; erectile dysfunction; decreased libido; and ejaculatorydysfunction; and weight gain.

Latanoprost, a prostaglandin analogue compound, approved for otherindications, has been demonstrated to enhance eyelashes and in a 2011study appeared to improve follicular activities. A NorthwesternUniversity sponsored trial (financed by Allergan) that was scheduled forcompletion in March 2017 included the following comment onClinicalTrials.gov:

-   -   In addition to our observations with topical bimatoprost on        fingernail growth, Wand and colleagues applied bimatoprost to        the base of the fingernails demonstrating a 16.9% increase in        fingernail growth from baseline, and a 10.4% increase from        baseline on untreated nail beds. Other than these two reports,        there are no studies addressing this topic to our knowledge        based on a Medline search for off-label use of this drug. Other        relevant studies have addressed increased hair and eyelash        growth with the prostaglandin agents. Researching the        biochemistry of the relationship of prostaglandins to hair and        nail growth, the final common pathway appears to be with protein        kinase C and the production of tropocollagens.

This trial of which the outcome is not known here supports continuedresearch and conclusions presented in support of credibility of thepresent invention.

Minoxidil is an example of an accidental drug. During trials and use forcontrolling blood pressure, hair growth was a noted side effect. Thisapparently results from increasing the anagenic phase at the expense ofthe telegenic phase by activating PGHS 1 (prostaglandin endoperoxidesynthase-1) in your system, helping to promote hair growth. However,side effects include skin irritation, itching, contact dermatitis,hives, swelling and sensitivity. Minoxidil is available as a topicalfoam or solution for rubbing or massaging into the skin of the scalp.

Male hormones, especially DHT and analogues, are involved in causingthese alopecic changes. The level of the classic male hormone,testosterone, is indistinguishable between men with or without apparentbaldness. In alopecia, cells in the skin of the scalp converttestosterone into DHT. These regional HFs become more sensitive to DHT,which then causes the HFs to shrink into the resting phase.

Saw palmetto is an effective anti-androgen. It acts in a similar waythat Propecia does. Firstly, it lowers levels of DHT in the body byBlocking 5 α-reductase. Secondly, Saw palmetto blocks receptor sites oncell membranes required for cells to absorb DHT. Saw palmetto has beennoted for its anti-oxidative and anti-inflammatory effects whensupported with selenium and/or lycopene, especially plant derivedlycopene, a non-flavonoid plant pigment.

Several flavonoid pigments including isoflavones can contribute to hairrestoration or regrowth, e.g., by decreasing the length of the telegenicphase. Isoflavones are members of the larger family of compounds, knownas flavonoids, which also includes flavones, flavanones, and flavans.These compounds are characterized by their phenyl side-chain, with avariable number of hydroxyl or other groups. Flavonoids with knownhormonal influence include, but are not limited to: Genistein, BiochaninA, Luteolin, Daidzein, Naringenin, 7-Hydroxyflavone, 6-Hydroxyflavanone,Resveratrol, 6-Bromo-2-naphthol, Chrysin, Apigenin, 6-Hydroxyflavone,Morin, Fisetin, Quercetin, 7,8-Dihydroxyflavone, 4′-Hydroxyflavanone,7-Hydroxyflavanone, Apigenin, Fisetin, Naringenin, Chrysin, Luteolin,Morin, etc. The specific mechanisms of action have not been proven formost of these compounds. Many combine an anti-androgenic and/oranti-estrogenic effect with anti-oxidant activity. Several haveinvolvement in the arachidonic cascade. Such compounds may be used assupportive compounds for hair growth formulations of the instantinvention.

Several thousand flavonoid compounds have been identified. Many aresuggested at various websites for incorporation into food supplements.Such popular compounds include, but are not limited to:3,3′,4′,5,7-pentahydroxyflavone,2-(4-hydroxy-3-propoxy-phenyl)-chroman-3,5,7-triol,2-(3-hydroxy-4-propoxy-phenyl)-chroman-3,5,7-triol;2-(3-ethoxy-4-hydroxy-phenyl)-chroman-3,5,7-triol,2-(4-ethoxy-3-hydroxy-phenyl)-chroman-3,5,7-triol,2-(3,4-dihydroxy-phenyl)-3-propoxy-chroman-5,7-diol, methyl4-((2R,3R)-3-hydroxy-5,7-dimethoxychroman-2-yl)-2-methoxybenzoate,methyl5-((2R,3R)-3-hydroxy-5,7-dimethoxychroman-2-yl)-2-methoxybenzoate,(4-((2R,3R)-3-hydroxy-5,7-dimethoxychroman-2-yl)-2-methoxyphenyl)(4-methylpiperazin-1-yl)methanone,ethyl2-(4-((2R,3R)-3-hydroxy-5,7-dimethoxychroman-2-yl)-2-methoxyphenoxy)acetate,ethyl2-(5-((2R,3R)-3-hydroxy-5,7-dimethoxychroman-2-yl)-2-methoxyphenoxy)acetate,2-(4-((2R,3R)-3-hydroxy-5,7-dimethoxychroman-2-yl)-2-methoxyphenoxy)aceticacid, ethyl2-(2-hydroxy-4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)phenoxy)acetate,ethyl2-(2-hydroxy-5-((2R,3R)-3,5,7-trihydroxychroman-2-yl)phenoxy)acetate,(2R,3R)-2-(3,4-dihydroxyphenyl)-3-methoxychroman-5,7-diol,((2R,3R)-2-(3,4-dihydroxyphenyl)-3-ethoxychroman-5,7-diol,(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl acetate,1-(((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl)oxy)ethylisobutyrate,W2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl)oxy)methyldiisopropylcarbamate,tert-butyl(W2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl)oxy)methyl)carbonate,4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene dioctanoate,(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl octanoate,(2R,3R)-2-(3,4-diacetoxyphenyl)chroman-3,5,7-triyl triacetate,4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene diacetate,4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene diacetate,(2R,3R)-2-(3,4-dihydroxyphenyl)-3-methylchroman-3,5,7-triol, etc. Oneexample of a patent extensively featuring flavonoids is U.S. Pat. No.9,187,744, the contents of which are incorporated in their entirety byreference.

The cannabis plant itself contains flavonoids including, but not limitedto: apigenin, luteolin, quercetin, kaemferol orientin, vitaxin,luteolin-7-O-glucoside, apigenin-7-O-glucoside cannflavins A and B,camphene, α-terpineol, α-eudesmol, α-selinene, fenchone, terpinolene,etc. Several, including luteolin, have been shown to inhibit PGD₂ orenhance an alternate pathway, e.g., PGE production, to divert PGD₂ fuelto alternate outcomes. Including such compounds in the product reducesor eliminates the telogenic enhancement effect seen in the presence ofexcess PGD₂.

For example, luteolin is marketed on the web as a supplement formultiple benefits, including as an anti-oxidant, mast cell activationinhibitor (possibly by blocking PGD₂ effect), free radical scavenger,histamine release blocker, GM-CSF release inhibitor, inhibitor of niacinflush. Luteolin and other flavonoids are available in small quantitiesin foods such as: celery, green pepper, thyme, perilla, chamomile tea,carrots, olive oil, peppermint, rosemary, navel oranges, and oregano. Ingeneral, PGD₂ inhibitors were formulated for use in treatment ofallergic rhinitis, asthma, and other inflammatory disorders. In the pastfive years Luteolin and other PGD₂ inhibitors have been proposed as“cures for baldness”. Yet to date none have been successful. Luteolinhas been proposed for use in a home-made 5% topical solution ostensiblyfor anti-PGD₂. Simply stopping the PGD₂ effect apparently is notsufficient to return the follicular phasing to the anagenic dominantphase. However, the presence of PGD₂ also prevents removal of5α-reductase inhibition from returning the cycle to anagenic dominance.Thus a preferred embodiment of the present invention features a nitricoxide activation and elimination or reduction of DHT and PGD₂ effects.Resveratrol, a natural phytocompound, selectively inhibits COX1 andblocks PGD₂ effects that support the telogenic phase over anagenic. Thusresveratrol with one or more nitric acid inducing compounds is part ofone preferred embodiment.

In a typical presentation, hair begins to recede at the temples and onthe crown of the head. A thinning hair region destined to become thebald patch gradually develops in the top-middle of the scalp. Thereceding regions from the temples and the bald patch spreading from thecrown gradually expand to join together, often leaving an island patchat the front. This island patch, over time, thins as well.

Alopecia treatment requires prolonged compliance and patience. Thegradual emphasis shift towards anagenic phase at the expense oftelegenic phase does not present earth shattering results. Severalmonths treatment is typical before noticeable effect. Compliance lapse,even for a short period, may require a new restart in the phase shiftingprocesses. In the non-treatment interval, the follicles in the anagenicphase rapidly progress to catagenic phase and all the progress (thehair) becomes detached and falls out. Many months treatment benefit maybe lost in just a few weeks.

With this background the present invention provides at least onealternative hair maintenance/hair growth paradigm. The effect(s) ofcannabinoids (compounds that bind to and affect activity of at least oneendocannabinoid receptor) demonstrate complexity in this area ofbiology. Given that DHT is instrumental in development of androgenicalopecia and that endocannabinoids and many phyto cannabinoids have beenshown to interfere with DHT interacting with its receptor, one wouldexpect that cannabinoids, by blocking the DHT effect, would prevent,stop, or at least slow hairloss. But a paper published in 2007,“Inhibition of human HF growth by endo- and exocannabinoids” showed theopposite.

The authors report:

-   -   Δ⁹-tetrahydrocannabinol (THC), the psychoactive component of        marijuana, mimics the effects of numerous endogenous substances        (collectively referred to as endocannabinoids) by binding to        cannabinoid (CB) receptors. Centrally, these endogenous        molecules are involved in regulating, e.g., behavior and        learning, while their peripheral effects include the modulation        of immune and cardiovascular functions and the control of growth        normal and transformed cells as well as cell death and survival.        CB receptors reportedly are also found on human epidermal        keratinocytes in vitro, with conflicting data as to which types        (CB1, CB2) are actually expressed. Although activation of CB        receptors may suppress growth, murine skin tumors and human        melanomas and, furthermore, cannabinoids were suggested to        modify in vitro proliferation and differentiation of transformed        keratinocytes, it is unclear whether CB receptors are        functionally important in normal human skin physiology.    -   The organ culture of human scalp hair follicles (HF) in the        growth stage of the hair cycle (anagen VI), which continue to        grow rapidly after microdissection and produce hair shafts in        vitro at almost the in vivo-speed seen on the human scalp, is        ideally suited to follow-up the above reports of        growth-modulatory effects of CB receptor ligands in the human        system. Employing this assay, we had already shown, e.g., that        vanilloid receptor-1 (TRPV1) agonists (such as capsaicin)        operate as potent inhibitors of human hair growth. Arguing,        furthermore, that the HF is exquisitely sensitive to the effects        of psychoemotional stress; that THC is prominently incorporated        into human hair shafts; and that several psychotropic hormones        have recently been recognized to modulate human hair growth, we        now have asked whether the endocannabinoid system is also        involved in the control of human hair growth.    -   Since the cycling HF represents a prototypic, constantly        remodeled epithelial-mesenchymal interaction system that        switches between states of rapid epithelial proliferation        (anagen), apoptosis-driven organ involution (catagen), and        relative quiescence (telogen), the organ culture of human HF,        which continues to undergo the anagen-catagen transformation in        vitro, offers a highly instructive, easily accessible model for        probing the effects of test agents on complex human tissue        interaction systems. Therefore, as an integral part of the        ongoing exploration of the intriguing “nonclassical”        neuro-endocrine role of the skin both under physiological and        pathological conditions, the human HF organ culture promised to        offer an ideal, physiologically and clinically relevant general        model system for dissecting the as-yet-unclear functions of        cannabinoids in the control of human cell growth and death in        situ.

The authors provide evidence that: 1) N-arachidonoylethanolamide(anandamide, AEA) significantly (P<0.05) and dose-dependently inhibitedhair shaft elongation and hair matrix keratinocyte proliferation. 2) CB₁binding activity is found in the HF epithelium, concentrated in theouter root sheath keratinocytes (but not so much in the fibroblasts ofthe HF dermal papilla. 3) transcription of the CB₁ gene but not the CB₂gene was observed by RT-PCR in human scalp HFs. and 4) AEA stimulatesapoptosis of cultured human HF. When anagen and catagen phase resultswere compared, CB₁ but not CB₂ transcription and expression areupregulated in catagen phase. Taken together these data suggestcannabinolic activity is important in phase timing and maintenance, CB₁,and not CB₂ is the more relevant cannabinoid receptor of this pair.Previous data had suggested another cannabinoid receptor, TRPV1, whenactivated inhibits hair shaft elongation (growth) and inducesapoptosis-driven catagen regression. Thus both TRPV1 and CB₁ arecandidates for action in hair loss and hairline regression.

This paper also reports endocannabinoid synthesis of CB₁ of dissected HFapproximated that of cardiac tissue, but that CB₂ synthesis was abouthalf that of cardiac. With respect to comparative effects of endogenouscannabinoid and those of THC this paper teaches: “THC significantlyinhibited hair shaft elongation in a dose-dependent fashion, suppressedproliferation of HF keratinocytes, and induced both hair matrixkeratinocyte apoptosis and premature catagen development. These data,therefore, suggest that exocannabinoids can mimic the hairgrowth-inhibitory effects of endocannabinoids.” These and other data ledauthors of this paper to conclude: “AEA (which may even be producedwithin human HF), and the—notoriously abused—exocannabinoid, THC, bothinhibit human hair shaft elongation and induce apoptosis-driven HFinvolution (catagen) in vitro.”

The cannabinoid blockade of the DHT driven androgenic alopecic effectswould suggest that applying exocannabinolic compounds or increasingendocannabinoid synthesis. However, in view of this 2007 paper and othersimilar teachings, the DHT inferred understanding that exposure of ascalp HF to an endo- or exo-cannabinoid would result in noticeableincrease in hair growth, including at least either number of activefollicles or hair length is shown to be faulty.

AEA and other cannabinoids exert their impacts in various manners. Oneimportant manner, especially with respect to HF is production of nitricoxide (NO). Both AEA and 2AG have been shown to be effective NOinducers. NO is probably most noted for its involvement in male erectionand as a target of erectile dysfunction drugs. NO is implicated as themain vasoactive nonadrenergic, noncholinergic neurotransmitter andchemical mediator of penile erection. In this capacity, NO activatessoluble guanylyl cyclase thereby initiating a chain of events thatcauses the smooth muscle of corpora cavernosa to relax and absorb blood.Released by nerve and endothelial cells in the corpora cavernosa of thepenis, NO activates soluble guanylyl cyclase, which increases3′,5′-cyclic guanosine monophosphate (cGMP) levels.

In addition to modulating NO levels, AEA also mediates the inhibition ofLPS-induced AA and prostaglandin apparently through a CB₂ activationpathway. In contrast, 2AG itself may serve as an AA precursor formetabolism by COX2 to PGE₂ countering PGD₂ synthesis.

Activation of CB₁ and/or CB₂ as well as TRPV1 results in increased NO.Increasing NO by these methods overcomes or bypasses the inhibitoryeffects of DHT and shifts HFs away from the catagenic phase and moretowards the anagenic.

AEA is also stored esterified to phosphatidylethanolamines and isreleased by the action of phospholipase D. AEA or another cannabinoid ofchoice may be delivered as the drug itself or as a pro-drug, e.g., AEAmay be effectively delivered as, for example, a pro-drugC20:4-N-arachidonoyl-phosphatidylethanolamine for conversion to AEA bythe a/J3-hydrolase 4 pathway; a prodrugC20:4-N-arachidonoyl-phosphatidylethanolamine for conversion to AEA bythe soluble phospholipase A2 pathway; a pro-drugC20:4-N-Arachidonoyl-phosphatidylethanolamine for conversion to AEA bythe protein tyrosine phosphatase 22/SH2-containinginositol-5-phosphatase pathway; a pro-drugC20:4-N-arachidonoyl-phosphatidylethanolamine for conversion to AEA bythe N-arachidonoyl-phosphatidylethanolaminephospholipase D pathway; AEAepoxide, already a CB₂ agonist, may be activated by cytochrome p450;etc.

Compounds such as secretoneurin that are known to stimulate NOproduction and release but have not yet been characterized to identifyall receptors to which it binds are considered as cannabinolic compoundswhen their application has results in line with those of knowncannabinoids. The term “cannabinoid active” is thus used to includecompounds with cannabinolic activity regardless of whether they havebeen identified as binding a cannabinoid receptor.

Inhibiting MAGL and/or FAAH, preferably by topical application, butalternatively by systemic application can prolong the effects of thehair stimulating cannabinoids.

Directing more AA which is often considered the rate limiting compoundto destinies other than PGD₂ is one means of minimizing the PGD₂anti-hair growth effect and will rebalance the HF metabolism backtowards the anagenic phase. In this vein, a membrane-bound glutathione(GSH)-dependent PGE₂ synthase (mPGES), continuation enzyme of thecyclooxygenase 2 (COX2)-mediated PGE₂ biosynthetic pathway is oneavailable tool. mPGES activity can be increased markedly at least inmacrophages in response to various proinflammatory stimuli. In thesecircumstances, mPGES was functionally coupled with the induced COX2 in amarked preference to the constitutively expressed COX1, especially whenAA was limited. Thus mild stress, such as a cannabinolic exposure mayhelp tilt the COX pathways away from PGD₂ production. Coupling this withan inhibitor more specific for COX2 will produce stronger beneficialanagenic effect. At least with AEA there is evidence that the PGE₂directed COX2 synthetic pathway is preferred over the COX1 pathwaycapable of making PGD₂. MIngYu, et al in “Synthesis of Prostaglandin E2Ethanolamide from Anandamide by Cyclooxygenase-2” report that AEA didnot serve as a substrate for COX1, but also that it did not compete withavailable AA in the COX1 pathway either. Excess or AEA undergoingremoval advantageously does not risk feeding the PGD₂ induced hairgrowth inhibition. PGD₂ binds the GPR44 receptor. Interfering with thisinteraction, e.g., by reducing or blocking ligand or receptor orinhibiting downstream effects of the receptor bonding may be used as anadjunct or alternative to cannabinoid induced NO. Resveratrol has beenshown to significantly suppress PGD₂ at low concentrations readilyobtainable through oral dosing. In general, use of the terms COX2inhibitor and COX1 inhibitor are meant to indicate that the inhibitorinhibits the numbered COX to a greater degree than the other COX. Forexample, valeryl salicylate would be considered a COX1 inhibitor becauseof its selective inhibition of the 1 isoform over that of the 2 isoform.Similar COX1 inhibitors include, but are not limited to: Cox-1 InhibitorII, FR122047 hydrate, resveratrol, SC 560, etc. (Although resveratrolhas capacity to inhibit COX2 also, resveratrol has greater inhibitorypotency against COX1.) Meloxicam sodium salt would be a COX2 inhibitor.While ibuprofen, ketoprofen and sulfidics would be considered COXinhibitors, COX1/2 inhibitors or COX1 and COX2 inhibitors.

Two kinetically distinct prostaglandin biosynthetic responses, theimmediate and delayed phases, imply involvement of different sets of thebiosynthetic enzymes whose expression and activation are tightlyregulated. In immediate PG biosynthesis, which occurs within severalminutes after stimulation with agonists that increase cytoplasmic Ca′levels, cytosolic phospholipase A2 (cPLA2) is required for supplyingmembrane sourced AA to COX1. In the delayed and prolonged PGbiosynthesis, which proceeds for a long time period after a stimulus,COX2, is an absolute requirement irrespective of the constitutivepresence of COX1. cPLA2 and several inducible secretory phospholipase A2isozymes cooperatively contribute to supply the AA to COX2. Thispreference of COX2 over COX1 may rest in the ability of COX2 tometabolize lower levels of AA to PGH₂ than the higher [AA] required forCOX1-directed catalysis. Bimaprost (discussed above as an eyelashthickener) appears to work through this effect. There is evidence thatat least some stress inducers not only divert AA to PGE₂ production, butalso induce another parallel AA consuming pathway to produceprostacyclin (PGI₂).

In the last decade or so we have come to recognize that prostaglandin D2(PGD₂) plays a primary role in hair loss. Scalp mast cells produce thisprostaglandin. Two to three fold increases in scalp PGD₂ are reported inbald individuals. Like the endogenous endocannabinoids, PGD₂ synthesisincludes arachidonic acid (AA) as a raw material in its syntheticpathway.

Arachidonic acid is acted on by a cyclooxygenase (COX1 or COX2) to formprostaglandin G₂ (PGG₂) which is rapidly COX converted to PGH₂. PGH₂ isa source of thromboxanes (e.g., TXA₂) (thromboxin synthase), PGD₂, PGE₂,PGF₂ and PGI₂ (prostacyclin synthase).

Two enzymatic steps are performed on the COX to convert AA to PGH₂. Acyclooxygenase portion catalyzes the conversion of AA to PGG₂ followedby peroxidase activity that reduces PGG₂ to PGH₂. COX1 and COX2 are twoknown isoforms capable of converting AA to PGH2 through a similarcatalytic site and mechanism. A third Cox isoform, COX3, is encoded inthe COX1 gene but with retention of intron 1 in the mRNA. Thephysiological function of this third isoform or possible other COXisoforms is unknown.

COX1 is constitutively expressed in most tissues and may regulatevarious homeostatic functions there. COX2 is inducible in many tissuesand when induced regulates PG production during several acute responsessuch as inflammation. In general, non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin inhibit both COX1 and COX2. But inhibitors moreselective for either COX1 or COX2 are available and under development.

After PGH₂ is synthesized the wide variety of PGs and related compoundsincluding, but not limited to: thromboxanes, PGD₂, PGE₂, PGF₂, PGI₂,etc., can be produced in accord with the specific PG synthase enzymespresent. For example, PGF-synthase enzyme has been cloned and is amember of the aldo-keto reductase family of enzymes that includes20α-hydroxysteroid dehydrogenase.

COX2-dependent biological responses has received much attention in thepast few years, because numerous pharmacological, biological and geneticstudies have suggested that this inducible COX isozyme is involved invarious human diseases, including inflammation and cancer and in atransformational patent case involving the University of Rochester.Generally, the main PG species produced during the delayed or inducedresponse is PGE₂. Since COX2 inhibitors would reduce PGE₂ moreprofoundly than other PGs (e.g., PGD₂), COX2 inhibition is not apreferred adjunct to the present invention unless this increased PGD₂synthesis is overcome or avoided.

PGES activity can be found in both cytosolic and membrane-associatedfractions of most cells and tissues. This enzyme uses the anti-oxidantcompound glutathione (GSH) as a cofactor for its catalytic effect. Thefirst isolated and characterized PGES however showed preferentialfunctional coupling with COX1.

A human microsomal GST-like 1 (MGST-L1) has now been identified andcharacterized as a member of the MAPEG (membrane-associated proteinsinvolved in eicosanoid and GSH metabolism) superfamily. MGST-L1 exhibitssignificant PGES activity and is inducible using IL-1 in some cells.MGST-L1 appears identical to a membrane-associated PGES (mPGES), whichhas now been detected in lipopolysaccharide (LPS)-stimulatedmacrophages. MGST-L1/mPGES expression is strongly induced in vitro andin vivo. This mPGES/MGST-L1 is preferentially linked with COX2 pathways,promoting delayed and induced immediate PGE₂ biosynthesis rather thanthe inhibitory PGD₂. Furthermore, sustained expression of both COX2 andmPGES/MGST-L1 leads to aberrant cell growth. Our results indicate thepresence of two segregated PGE2-biosynthetic routes, thecPLA2-COX1-cPGES/p23 and cPLA2-COX2-mPGES/MGST-L1 pathways, in the samecell.

The two main cannabinoids produced in mammalian, including human, bodytissues are anandamide aka N-arachidonoylethanolamine (AEA). Both AEAand the phytocannabinoid, THC, have similar agonistic potency withrespect to CB₁. THC is more potent with respect to the CB₂ receptor butapparently exerts its well-known psychotropic effects through the CB₁receptor.

AEA is also an exogenous phytocannabinoid found in many spices and foodssuch as chocolate. Endogenous AEA activity is increased bypalmitoylethanolamide (PEA) which apparently does not bind CB₁ or CB₂but may be additive or synergistic when both are present, possiblythrough AEA synthesis induction by PEA. One metabolic pathway for AEA isenzymatic oxygenation by cytochrome P450 hydroxylates and bylipoxygenases to yield hydroperoxy- and hydroxy-derivatives of AEA. AEAalso serves as a substrate for cyclooxygenase-2 resulting in the PGE₂derivative of AEA. An enzyme responsible for continuous removal of AEAand related cannabinoids is fatty acid amide amidohydrolase (FAAH).

The other predominant cannabinoid in mammals, especially in theneurological system is 2-Arachidonylglycerol (2AG). Whereas AEA has abinding preference for CB₁ over CB₂, 2AG has similar agonistic affinityfor each.

2AG can be metabolized rapidly to yield arachidonic acid and glycerol.Rapid elimination of 2AG from the extracellular fluid would beexpectedly advantageous given that 2AG exhibits potent biologicalactivities directed at or in diverse tissues and cells. Any misdirectedexcess 2AG might exert deleterious and undesirable effects. A capacityfor rapid clearance of 2AG soon after generation is essential to preventunwanted consequences.

2AG appears to be primarily metabolized at least in some tissues by amonoacylglycerol lipase, as are other monoacylglycerols. In similaritywith AEA, FAAH is available to metabolize 2AG as well. 2AG can bemetabolized to 2-arachidonoyl LPA through the action of a kinase(s) torecycle 2AG in the form of glycerophospholipids such as PI. COX2 and12-lipoxygenase can oxygenate 2AG to yield oxygenated products of 2AG(prostaglandins glyceryl ester and12(S)-hydroperoxyeicosa-5,8,10,14-tetraenoic acid glyceryl ester).

Use of topical PGE₂ was reported by Kapoor et al, 2008 wherein a gel(0.25 mg/g) commercially available as a sterile translucent gelpreparation containing dinoprostone 0.50 mg/2 g was applied 2×/day totreat vitilago. They report “PGE₂ enhances basic fibroblast growthfactor (bFGF) mRNA expression in a dose-dependent fashion”. Results ofthe study hoping to restore pigmentation to patches of light skin showsuccessful outcomes with a trend towards improved outcomes towards thecephalic portion as opposed to extremities.

Side effects of CB₁ activity including, but not limited to: reducedanxiety, increased stress tolerance, food craving. The drug, rimonabant,developed by Sanofi as a weight loss drug, a cannabinoid receptorblocker, was withdrawn from the European market because of possibleincreased depression and at least successful suicide. Though not proven,there is suggestive evidence that CB₁ and/or CB₂ activity may be animportant endogenous control on bouts of depression including someassociated with PTSD.

Haplosamate derivatives are the first naturally derived cannabinomimeticcompound belonging to steroid family. They represent another newchemical class of cannabinoid receptor ligands. This group of steroidsincludes but is not limited to: haplosamate A and haplosamate B.

Haplosamate A and desulfohaplosamate have opposite effects. HaplosamateA has strong affinity for CB₁. Desulfohaplosamate has higher affinityfor CB₂. The 7-monoacetylated derivative of haplosamate A exhibitsaffinity to both CB₁ and CB₂ cannabinoid receptors in comparison to itsparent compound. However, acetylation at C-4 or dialdehyde derivativeresults in the loss of affinity on both CB₁ and CB₂.

While less dramatic than anabolic steroid injection, activation of CB₁and CB₂ results in release of epinephrine, corticosteroids, and immunecalming IL-10, while decreasing pro-inflammatory IL-2. Steadysupplementation with one or more synthetic or phytocannabinoid haseffects that can be used to substitute for chronically usedcorticosteroid immune suppression, but will have a more natural controland fewer side effects. Cannabinoid mediated responses include a generalcalming of local (e.g., dermal, iliac, bowel, gastric, mucosal, etc.)pro-inflammatory mediators including, but not limited to:myeloperoxidase, CXCL8, IL-1β, TNF, etc. Cannabis has also been shown tosuppress the immune system by activating myeloid-derived suppressorcells (MDSCs). MDSCs may help dampen the hyperactive immune system.

A class of modulating biomolecules has been characterized as“endocannabinoids”. The name is derived from the receptors active inthis system that also being to products from the cannabis plant.Originally two cannabinoid receptors were recognized in humans/mammalsbecause THC, a psychoactive cannabinoid substance from Cannabis wasfound to interact with these proteins. These were dubbed: cannabinoidreceptor 1 (CB₁) and cannabinoid receptor 2 (CB₂). AEA and 2AG wererecognized as predominant endocannabinoids binding these receptors. CB₁immunoreactive neurons were found in close proximity to ileal Peyer'spatches and were localized in some submucosal blood vessels. However,subsequent discoveries have revealed other endobiologic compounds alsobinding these receptors and them additional receptors which interactwith AEA and 2AG and the additional recognized compounds withendocannabinoid activity.

GPR₅₅ and CB₁ receptors modulate each other's signaling properties.GPR55 forms heteromers with another 7× transmembrane spanning/GPCR whichthen interacts with CB₁. GPR55-CB₁ heterodimer acts as a modifiedcannabinoid receptor that cells form to modulate activities in responseto exogenous cannabinoid. This plasma membrane response is independentof cannabinoid effects on internal organelles including, but not limitedto: mitochondria, peroxisomes, endoplasmic reticulum, golgi, etc.

Palmitoylethanolamide (PEA) is an endocannabinoid especially capable ofdownregulating mast cell activation and inflammation. AEA is also aneffective endogenous agonist for the central cannabinoid receptor CB₁ onmast cells. PEA activity may be through CB₂ and other cannabinoidreceptors. PEA and AEA bind to CB₂ but AEA may be more effective whenbound to CB₁. This provides evidence that PEA and/or its derivatives maybe used to provide anti-inflammatory therapeutic strategies specificallytargeted at mast cells.

The endocannabinoid system (ECS) is an important lipid based signalingand immunomodulator system. Lipophilic compounds, those that can readilycross plasma membranes are prime activators of these endocannabinoidpathways. Research relating to medical uses of marijuana and traditionalmedicines has shown that at least compounds that bind CB₁ and CB₂participate in modulating many physiological responses including, butnot limited to: appetite, respiration, metabolism, inflammation,allergy, pain, neurotransmission, etc. The ECS is comprised of G-proteincoupled receptors (GPCRs) including, but not limited to: CB₁, CB₂,TRPV₁, TRPV₂, TRPV₃, TRPV₄, TRPA₁, TRPM₈, GPR₅₅, GPR₁₈, etc.

Two notable catabolic enzymes, fatty acid amide hydrolase (FAAH) andmonoglycerol lipase (MAGL), are involved in the breakdown of anandamideand 2AG, respectively. Simply put, less FAAH and MAGL means more AEA and2AG. So inhibitors of these catabolic enzymes, for example by nutmegextracts, slows breakdown and raises the available levels of AEA and 2AGgenerally boosting cannabinoid receptor signaling. FAAH and MAGLinhibition therefore can be used in reducing or managing pain, anxiety,hypertension and various inflammatory conditions.

In general, many plant species, especially those used for spices, haveanti-allergy/anti-inflammatory activities. E.g., nutmeg interacts withthe endocannabinoid system by inhibiting certain key enzymes thatcatabolize (break down) the two main endocannabinoids, anandamide and2AG.

URB597 inhibits FAAH, the principle enzyme involved in degrading thelipid molecule AEA into its arachidonoyl and ethanolamide components.FAAH is a significant step in the pathway for creating prostaglandinethanolamide compounds including D2 ethanolamide. Inhibiting FAAH raisesnatural AEA levels and leads to long-term cannabinoid receptoractivation and pain relief. URB937, is anotherp-hydroxyphenyl-O-arylcarbamate that targets FAAH. FAAH is alsoresponsible for the metabolism of other fatty acid amides e.g.,N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA). FAAHinhibition maintains or increases tissue levels of anandamide in vivo.

Examples of FAAH inhibitors include but are not limited to: AM374,ARN2508, BIA 10-2474, BMS-469908, CAY-10402, JNJ-245, JNJ-1661010,JNJ-28833155, JNJ-40413269, JNJ-42119779, JNJ-42165279, LY-2183240,cannabidiol, MK-3168, MK-4409, MM-433593, OL-92, OL-135, PF-622, PF-750,PF-3845, PF-04457845, PF-04862853, RN-450, SA-47, SA-73, SSR-411298,ST-4068, TK-25, URB524, URB597 (KDS-4103), URB694, URB937, VER-156084,V-158866, AM3506, AM6701, CAY10435, CAY10499, IDFP, JJKK-048,JNJ-40355003, JNJ-5003, JW618, JW651, JZL184, JZL195, JZP-372A, KML29,MAFP, MJN110, ML30, N-arachidonoyl maleimide, OL-135, OL92, PF-04457845,SA-57, ST4070, URB880, URB937, etc.

β-caryophyllene, a phytocannabinoid, and/or its oxides act as fullagonists of the CB₂-receptor where they exert anti-inflammatory andanalgesic effects that are mediated through CB₂, but not CB₁. Anotherphytocannabinoid, salvinorin A, from the plant species Salvia divinorumextract is a terpenoid that interacts with a cannabinoid receptor, notyet characterized that apparently forms only in inflammatory conditions.This uncharacterized receptor also acts as a κ-opioid receptor. Manysages produce similar compounds with some activity, but whose activitieshave not been followed in detail to identify receptor interactions.Myrcene is a major constituent of the essential oil of hops and appearsto be related to opioid “high” possibly by agonizing opioid receptors orpossibly by antagonizing opioid degradation. Plant sources are hops,verbena and cannabis. Myrcene is also found in lemongrass, thyme andmango. Echinacea contains multiple N-alkylamides that have cannabinoidmimetic effects.

Cannabigerol class: cannabigerolic acid (CBGA) (antibiotic);cannabigerolic acid monomethylether (CBGAM); cannabigerol (CBG)(antibiotic, antifungal, anti-inflammatory, analgesic); cannabigerolmonomethylether (CBGM); cannabigerovarinic acid (CBGVA);cannabigerovarin (CBGV).

Cannabichromene class: Cannabichromenic acid (CBCA); cannabichromene(CBC) (antibiotic, antifungal, anti-inflammatory, analgesic);cannabichromevarinic acid (CBCVA); cannabichromevarin (CBCV);Cannabidiolic acid (CBDA) (antibiotic); cannabidiol (CBD) ((antioxidant,anxiolytic, antispasmodic, anti-inflammatory, analgesic); cannabidiolmonomethylether (CBDM); cannabidiol C₄ (CBD-C4); cannabidivarinic acid(CBDVA); cannabidivarin (CBDV); cannabidiorcol (CBD-C1);Δ⁹-tetrahydrocannabinolic acid A (THCA-A); Δ⁹-tetrahydrocannabinolicacid B (THCA-B);6a,10a-trans-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol,(Δ⁹ tetrahydrocannabinol, THC) (analgesic, antioxidant, antiemetic,anti-inflammation); Δ⁹-tetrahydrocannabinolic acid-C4 (THCA-C4);Δ⁹-tetrahydrocannabinol-C4 (THC-C4); Δ⁹-tetrahydrocannabivarinic acid(THCVA); Δ⁹-tetrahydrocannabivarinic (THCV);Δ⁷-cis-isotetrahydrocannabivarin; Δ⁹-tetrahydrocannabiorcolic acid(THCA-C1); tetrahydro-cannabiorcol (THC-C1).

Δ⁸-tetrahydrocannabinol class: Δ⁸-tetrahydrocannabinolic acid (Δ⁸-TCA);Δ⁸-tetrahydrocannabinol (Δ⁸-THC).

Cannabicyclol class: cannabicyclol (CBL); cannabicyclolic acid (CBLA);cannabicyclovarin (CBLV).

Cannabielsoin class: cannabiesoic acid A (CBEA-A); cannabiesoic acid B(CBEA-B); cannabielsoin (CBE).

Cannabinol and cannabinodiol class: cannabinolic acid (CBNA); cannabinol(CBN); cannabinol methylether (CBNM); cannabinol-C4 (CBN-C4);cannabivarin (CBV); cannabinol-C2 (CBN-C2); cannabiorcol (CBN-C1);cannabinodiol (CBND); cannabidivarin (CBDV).

Cannabitriol class: cannabitriol (CBT);10-Ethoxy-9-hydroxy-Δ-6a-tetrahydrocannabinol (10-EHDT);8,9-dihydroxy-delta-6a-tetrahydrocannabinol (8,9-DHDT);cannabitriolvarin (CBTV); ethoxy-cannabitriolvarin (CBTVE).

Miscellaneous class: dehydrocannabifuran (DCBF); cannabifuran (CBF);cannabichromanon (CBCN); cannabicitran (CBT);10-oxo-Δ-6a-tetrahydrocannabinol (OTHC); Δ⁹-cis-tetrahydrocannabinol(cis-THC);3,4,5,6-tetrahydro-7-hydroxy-α-α-2-trimethyl-9-n-propyl-2,6-methano-2H-1-benzoxocin-5-methanol(2H-iso-HHCV); cannabiripsol (CBR); Trihydroxy-Δ⁹-tetrahydrocannabinol(triOH-THC).

LEA, PEA and OEA will bind to one or more of the endogenous cannabinoidreceptors, but they are also important because they maintain AEAactivity through their inhibition of the FAAH enzyme that is responsiblefor degrading AEA. N-alkylamides exert selective effects on the CB₂, andhave been shown to exert anti-inflammatory effects similar to AEA.Echinacea contains multiple N-alkylamides that have mimetic effects.

At least 20 flavonoid compounds, including, but not limited to:apigenin, quercetin, canniflavin A and canniflavin B, β-sitosterol,vitaxin, isovitexin, kaemferol, luteolin and orientin have beenidentified in the cannabis plant.

Magnolol, a biphenyl neolignan from Magnolia officinalis, magnolol actsas a partial agonist for CB₂, while honokiol is less potent but has fullagonistic activity at CB₁ and antagonistic properties at CB₂.Malyngamide B binds both CB₁ and CB₂, with moderate potencies as anagonist anti-inflammatory compound. While many cannabinoids supportnitric oxide (NO) production magnolol inhibits NO production with anIC₅₀˜6.2 μM.

NO is a free radical formed from L-arginine by converting it toL-citrulline via nitric oxide synthase (NOS) enzymes. The reactionproduct of NO with superoxide generates potent oxidizing agent,peroxynitrite which is the main mediator of tissue and cellular injury.When NO and O₂ ⁻ (nitric oxide free radical and superoxide anion freeradical) react peroxynitrite, a powerful oxidant capable of elicitingmajor cell and tissue injury, results. Despite this and other possibledeleterious outcomes, over the past four or five decades NO has beenacknowledged as a molecule of extreme importance in intracellular andintercellular communication, slowing proliferation of, for example,smooth muscle cells; controlling platelet and endothelial adhesion;acting as a neurotransmitter; modulating mitochondrial membranepermeability; etc. As examples of NO activities, NO induced PGE₂activity is part of the pathway through which the body sensesdehydration and signals remedial actions across multiple organs andsystems; responding to toxic events such as ethanol intoxication; arelation between cannabinoids and NO is part of joint cartilagemaintenance; NO is one compensatory compound involved in multiplepathways to minimize deleterious effects of heart failure; mtNOS appearsactive in inducing apoptosis in infected cells; NO is closely controlledin a recovering cell following an ischemic event, sometimes support cellrecovery while sometimes encouraging apoptosis; NO is part of the pathfor restoring proper protein folding through its actions on at leastHSP70; NO controls mitochondrial growth, synthesis and fusion followingintense exercise; NOS activity is induced following sleep deprivationreleasing NO in support of REM sleep stages.

NO has a short half-life in aqueous solution undergoing reactions withsuperoxide as mentioned above to form peroxynitrite, auto-oxidize inwater to form nitrous anhydride (N₂O₃), acidify to form nitrous acid andnitrite, lose the radical electron to form nitrosonium, etc. NO isparticularly reactive with heme irons, e.g., to control lipid oxygenasereactions. NO is an important intercellular messenger through itsactivation of soluble guanyl cyclase leading to enzymatic and ionchannel activations. NO reversibly inhibits many enzymes, especiallyheme containing or free radical activated enzymes; when involved inapoptosis, NO is involved in multiple paths including, but not limitedto: mitochondrial membrane permeability, mitochondrial fusion/fissionbalance, production of ROS and other oxidative compounds, activation ofASK1-JNK1 branch point, etc.; the NFκB ligand, RANKL is up regulated inresponse to depressed calcium levels; stress induced NO helps thecytoskeleton direct proteins and other biomolecules to the golgi andother organelles.

The relation by which cannabinoids, e.g., AEA, mediate intracellular andextracellular events through activating NO synthesis is well-conservedevolutionarily. Plants, invertebrate animals and vertebrate animals alldemonstrate this relationship. The evidence generally involves assessingNO signaling changes upon exposure to a cannabinoid compound andblocking these changes with specific inhibition of a relevant NOSenzyme. The activities and enzymes may differ between organisms, but theendocannabinoid/NOS relationship and resultant NO production areconserved. The ubiquity of applications of the NO signaling systems isfurther evidenced by the incorporation of an NOS enzyme in themitochondrial inner membrane where it is implicated in peroxynitriteformation and cytochrome c oxidase reaction rates.

Cannabinolic phyto-compounds or derivatives include but are not limitedto: abinene, α-pinene, 4,8-dimethyl-1,7-nonadien-4-ol,2-hydroxy-4-methyl-valeric, acid methyl ester, octanal, O-cymene,eucalyptol, α-phellandrene, cis-sabinene, hydroxide, myrcenol,terpinen-4-ol, α-terpineol, β-thujene, ç-terpinene, trans-α-ocimene,carveol, β-citral, guanidine, geraniol, bornyl, acetate, β-pinene,thymol, geranic, acid methyl ester, α-terpinyl acetate, d-limonene,eugenol, geranyl acetate, dihydrocarvyl acetate, α-ylangene,cis-dodec-5-enal, 3-phenyl-2-propenoic, acid methyl ester, β-elemene, c,vanillin, epoxy-α-terpenyl acetate, butanoic, acid 2-methyl-,3,7-dimethyl-2,6-octadienyl ester,1-methyl-4-(1-acetoxy-1-methylethyl)-cyclohex-2-enol,1,2,3,4,4a,5,6,8a-octahydro-4a,8-dimethyl-2-(1-methylethenyl)-,[2r-(2à,4aà,8aá)]-naphthalene, p-mentha-1(7),8-dien-2-ol, ç-muurolenehydroxy-α-terpenyl acetate, nerolidol, geranyl bromide,(−)-α-panasinsene, pyrocatechol, ç-elemene, 9,10-dehydro-isolongifolene,à-calacorene, cis-verbenol acetic, acid,1-methyl-1-(4-methyl-5-oxo-cyclohex-3-enyl)ethyl ester,alloaromadendrene, z,z-2,6-dimethyl-3,5,7-octatriene-2-ol,4-epi-cubedol, 2-oxabicyclo[2.2.2]octan-6-ol, 1,3,3-trimethyl-acetate,patchoulane, farnesol, caryophyllene oxide, cis-lanceol, ledeneoxide-(ii), farnesol acetate, 6-epi-shyobunol, falcarinol, phytol,aromadendrene oxide-(2), heptacosane, longipinene, epoxide,hentriacontane, decamethyl-cyclopentasiloxane, geranyl, isobutyl,hexamethyl-cyclotrisiloxane, 1-docosene, tetratetracontane,dodecamethyl-cyclohexasiloxane, etc.

Supplementation with cannabinoid active substances can facilitate thecells' and the organisms mitochondrial rebalancing.

Marihuana inhibits dihydrotestosterone binding to the androgen receptor.

According to the study, bald men tend to have an abnormal amount of aprotein called prostaglandin D2 on their scalps. This protein and itsderivatives block hair growth.

The conversion of AEA to prostaglandins (PG) including, but not limitedto: D2, E2, F2, G2, H2, I2, J2, etc. antagonizes the cadherininflammation calming functions. H2 is readily converted to D2, E2, F2,I2, F1α, and thromboxanes. D2 is a major prostaglandin produced by mastcells and binds to the receptors PTGDR (DP1) and CRTH2 (DP2). Thisrecruits Th2 cells, eosinophils, and basophils leading to aninflammatory response. D2 is a critical component in development ofallergic disease responses such as asthma and therefore is of primeinterest. E2/F2, I2/F1α and thromboxanes are separate production branchoffshoots from H2 that can compete with D2 production.

PGD₂ inhibitors are a class of chemical components that exert aninhibitory effect on the synthesis, release, or effects of PGD₂ in vitroor in vivo. PGD₂ inhibition was researched in the context of treatingasthma, allergic rhinitis and similar disease states. Such compounds andthose for example listed and described in US Application 20150072963, USApplication 20160346186 and/or US Application 20110021599, the contentsof each where they relate to PGD₂ inhibitors herein incorporated in theentirety of their relevant disclosures by reference, advantageouslyformulated or reformulated for topical administration are preferredcomponents of applications of the present invention.

Prostaglandin D2-glycerol ester was found to decrease macrophageactivation, and this effect was dependent on ABDH[HD]6 activity(α/β-hydrolase domain 6; see also ABHD 12) that revert 2AG (secondcannabinoid after AEA).

In gut tissue, activation of CB₁ receptors by cannabinoids,plant-derived, endogenous or synthetic, effectively reduces both gastricacid secretion and gastric motor activity, and decreases the formationof gastric mucosal lesions induced by stress, pylorus ligation,nonsteroidal anti-inflammatory drugs (NSAIDs) or alcohol, partly byperipheral, partly by central mechanisms. Similarly, indirect activationof cannabinoid receptors through elevation of endocannabinoid levels byglobally acting or peripherally restricted inhibitors of their ligandmetabolizing enzymes (FAAH, MAGL) or by inhibitors of their cellularuptake reduces the gastric mucosal lesions induced by NSAIDs in a CB₁receptor-dependent fashion.

Use of cannabinolic compounds for medical treatments is growing. Alreadyseveral plant-derived cannabinoids are used in the medical practice,such as Δ⁹-THC (dronabinol) and its synthetic analogue, nabilone,against chemotherapy-induced nausea and emesis, and as appetitestimulants (e.g. in AIDS patients). CBD combined with Δ⁹-THC(nabiximols) is used to relief neuropathic pain and spasticity inmultiple sclerosis, and as an adjunctive analgesic treatment in advancedcancer pain.

Synthetic cannabinoid derivatives may differ from the natural ones inseveral aspects, e.g. in pharmacokinetic properties or in bindingaffinity to the different cannabinoid receptors. For examplemethanandamide, an amidase resistant chiral analogue of AEA possesseshigher metabolic stability than its parent compound. WIN 55,212-2, anaminoalkylindole derivative is a potent agonist at both CB₁ and CB₂receptors and one of the most frequently used synthetic cannabinoids. Itproduces effects similar to those of Δ⁹-THC, although it has an entirelydifferent chemical structure. Differences in binding affinity todifferent cannabinoid receptors may result in selective agonists at CB₁or CB₂ receptors. For example, ACEA (arachidonoyl-2′-chloroethylamide)prefers CB₁ receptors, while JWH 133(3-(1′,1′-Dimethylbutyl)-1-deoxy-delta8-THC), or GP1a(1-(2′,4′-dichlorophenyl)-6-methyl-N-piperidine-1-yl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide)are selective for CB₂ receptors. Moreover, differences in distributionmay result either in global actions or peripherally restricted effects,such as the peripherally acting CB_(1/2) agonist AZD 1940 and AZD 1704.

Activation of CB₁ and CB₂ receptors can be achieved not only throughbinding by the natural and synthetic cannabinoids provided, but alsosecondarily, by elevating of the level of existing endocannabinoids inthe vicinity of cannabinoid receptors, e.g., by blocking theirdegradation and/or uptake. AEA and 2AG levels are regulated in vivo bycatabolic enzymes, e.g., FAAH, which hydrolyzes AEA into AA andethanolamine, and monoacylglycerol lipase (MAGL), which is the maineffector of 2AG hydrolysis. However, we must remember additionalenzymes, e.g., the COX, lipooxygenases and cytochrome P450 enzymes thatis a given circumstance may also have or be induced to have asignificant role in degradation of the endocannabinoids. Extracellularcannabinoids are constantly removed from circulation or interstitium butuptake into the cells and metabolism.

To date over 120 cannabinoids, the so-called phytocannabinoids (pCB),have been isolated from the cannabis plant. Most phytocannabinoids sharecommon structural features that include a dibenzopyran ring and ahydrophobic alkyl chain. The most abundant cannabinoids in the plant areΔ⁹-tetrahydrocannabinol (Δ⁹-THC or simply, THC), Δ⁸-tetrahydrocannabinol(Δ⁸-THC), cannabinol (CBN), cannabidiol (CBD), cannabigerol (CBG), andcannabichromene (CBC), Δ⁹-tetrahydrocannabivarin (THCV), cannabivarin(CBV), cannabidivarin (CBDV). Despite their lower presence in the plant,other phytocannabinoids such as cannabinodiol (CBND), cannabielsoin(CBE), cannabicyclol (CBL) and cannabitriol (CBT) have also been thesubjects of study in the last decades.

The different phytocannabinoids show different relative affinities forCB₁ and CB₂ receptors. In addition, over the last years, receptortargets outside the classic endocannabinoid system have been identifiedas binding sites and action centers for certain plant cannabinoids.These compounds have been shown to interact with other G-protein coupledreceptors such as the putative cannabinoid receptors GPR55 or GPR18, andother well-known GPCRs such as the opioid or the serotonin receptors. Inaddition, several papers have reported the ability of certainphytocannabinoids to modulate nuclear receptors, ligand-gated ionchannels or transient receptor potential (TRP) channels, among others.

For example, in the synthetic realm, SR141716A, the first reported CB1antagonist displays nanomolar CB₁ affinity (Ki=1.98±0.13 nM), but verylow affinity for CB₂. SR141716A has acts as a competitive antagonist andan inverse agonist in cells transfected with exogenous CB₁ receptor, andin cells endogenously expressing CB₁. Several additional CB₁ antagonistshave been reportedly synthesized, including, but not limited to:LY-320135, 0-1184, CP-272871, URB447, a class ofbenzocycloheptapyrazoles, a novel series of 3,4-diarylpyrazolines andbiarylpyrazolyl oxadiazoles. A first peptide CB₁ inverse agonist,hemopressin (HP; PVNFKFLSH) (SEQ ID No. 1), has also been reported.

Additional endocannabinoids identified to date include N-arachidonoyldopamine (NADA) and virodhamine. N-arachidonoyl-dopamine (NADA) is anendogenous “capsaicin-like” substance in mammalian nervous tissues. NADAactivates cannabinoid CB₁ receptors, but not the dopamine D₁ and D₂receptors. Virodhamine is arachidonic and ethanolamine joined by anester linkage.

The CB₂ receptor in general recognizes the same structural groups ofcannabinoid agonists as CB₁, with differing affinities in some cases,for example CB₂ has higher affinity for aminoalkylindoles.

The discussion of specific combinations of treatments, protocols,compounds and/or exemplary uses are for illustration of how the presentinvention might be applied in one or more specific circumstances. Suchare not intended to exclude other potential embodiments not specificallydiscussed herein.

Application 62/609,384 and Ser. No. 15/954,582 are hereby incorporatedby reference in their entireties. The CRF submitted herewith as a .txtdocument has identical sequence disclosure for the 3 applications, thecontent of which is incorporated by reference in its entirety and isreproduced on the following page.

1. A therapeutic product for biologically stimulating, or preventing biological interference with, hair growth on the scalp, said product comprising i) a nitric oxide inducing cannabinoid active compound and at least one separate compound ii) a hair growth augmenter selected from the group consisting of: a 5-α reductase inhibitor, an androgen receptor blocking compound in active or pro-active form, a flavonoid compound, a PGD₂ activity inhibitor, a compound that decreases PGD₂ synthesis, and a cannabinoid receptor synthesis inducer.
 2. The therapeutic product of claim 1 wherein said hair growth augmenter comprises at least one compound presenting a plurality of said Markush group characteristics.
 3. The therapeutic product of claim 1 wherein administration to the scalp decreases the time length of the telegenic phase of a significant number of hair follicles (HF)s.
 4. The therapeutic product of claim 1 wherein administration to the scalp decreases hair growth interference wrought by dihydrotestosterone.
 5. The therapeutic product of claim 1 wherein administration to the scalp decreases hair growth interference wrought by prostaglandin D₂.
 6. The therapeutic product of claim 1 wherein said nitric acid inducing cannabinoid compound agonizes a receptor selected from the group consisting of: CB₁, CB₂, TRPV₁, TRPV₂, TRPV₃, TRPV₄, TRPA₁, TRPM₈, GPR₅₅ and GPR₁₈.
 7. The therapeutic product of claim 1 wherein ii) comprises at least one flavonoid.
 8. The therapeutic product of claim 7 wherein said flavonoid is selected from the group consisting of: apigenin, quercetin, canniflavin A and canniflavin B, β-sitosterol, vitaxin, isovitexin, kaemferol, luteolin and orientin.
 9. The therapeutic product of claim 7 wherein said flavonoid is selected from the group consisting of: 3,3′,4′,5,7-pentahydroxyflavone, 2-(4-hydroxy-3-propoxy-phenyl)-chroman-3,5,7-triol, 2-(3-hydroxy-4-propoxy-phenyl)-chroman-3,5,7-triol; 2-(3-ethoxy-4-hydroxy-phenyl)-chroman-3,5,7-triol, 2-(4-ethoxy-3-hydroxy-phenyl)-chroman-3,5,7-triol, 2-(3,4-dihydroxy-phenyl)-3-propoxy-chroman-5,7-diol, methyl 4-((2R,3R)-3-hydroxy-5,7-dimethoxychroman-2-yl)-2-methoxybenzoate, methyl 5-((2R,3R)-3-hydroxy-5,7-dimethoxychroman-2-yl)-2-methoxybenzoate, (4-((2R,3R)-3-hydroxy-5,7-dimethoxychroman-2-yl)-2-methoxyphenyl)(4-methylpiperazin-1-yl)-methanone, ethyl 2-(4-((2R,3R)-3-hydroxy-5,7-dimethoxychroman-2-yl)-2-methoxyphenoxy)-acetate, ethyl 2-(5-((2R,3R)-3-hydroxy-5,7-dimethoxychroman-2-yl)-2-methoxyphenoxy)acetate, 2-(4-((2R,3R)-3-hydroxy-5,7-dimethoxychroman-2-yl)-2-methoxyphenoxy)acetic acid, ethyl 2-(2-hydroxy-4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)phenoxy)acetate, ethyl 2-(2-hydroxy-5-((2R,3R)-3,5,7-trihydroxychroman-2-yl)phenoxy)acetate, (2R,3R)-2-(3,4-dihydroxyphenyl)-3-me-thoxychroman-5,7-diol, ((2R,3R)-2-(3,4-dihydroxyphenyl)-3-ethoxychroman-5,7-diol, (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl acetate, 1-(((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl)oxy)ethyl isobutyrate, (((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihy-droxychroman-3-yl)oxy)methyl diisopropylcarbamate, tert-butyl(W2R,3R)-2-(3,4-dihydroxy-phenyl)-5,7-dihydroxychroman-3-yl)oxy)methyl)carbonate, 4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene dioctanoate, (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl octanoate, (2R,3R)-2-(3,4-diacetoxyphenyl)chroman-3,5,7-triyl triacetate, 4-((2R,3R)3,5,7-trihydroxychroman-2-yl)-1,2-phenylene diacetate, 4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene diacetate and (2R,3R)-2-(3,4-dihydroxyphenyl)-3-methylchroman-3,5,7-triol.
 10. The therapeutic product of claim 1 wherein said nitric acid inducing cannabinoid compound is selected from the group consisting of: cannabichromenic acid (CBCA); cannabichromene (CBC); cannabichromevarinic acid (CBCVA); cannabichromevarin (CBCV); cannabidiolic acid (CBDA); cannabidiol (CBD); cannabidiol monomethylether (CBDM); cannabidiol C₄ (CBD-C4); cannabidivarinic acid (CBDVA); cannabidivarin (CBDV); cannabidiorcol (CBD-C1); Δ⁹-tetrahydrocannabinolic acid A (THCA-A); Δ⁹-tetrahydrocannabinolic acid B (THCA-B); 6a,10a-trans-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol, Δ⁹-tetrahydrocannabinol (THC); Δ⁹-tetrahydrocannabinolic acid-C4 (THCA-C4); Δ⁹-tetrahydrocannabinol-C4 (THC-C4); Δ⁹-tetrahydrocannabivarinic acid (THCVA); Δ⁹-tetrahydrocannabivarinic (THCV); Δ⁷-cis-isotetrahydrocannabivarin; Δ⁹-tetrahydrocannabiorcolic acid (THCA-C1) and tetrahydrocannabinol (THC-C1).
 11. The therapeutic product of claim 1 wherein said nitric acid inducing cannabinoid compound is selected from the group consisting of: cannabicyclol (CBL); cannabicyclolic acid (CBLA) and cannabicyclovarin (CBLV).
 12. The therapeutic product of claim 1 wherein said nitric acid inducing cannabinoid compound is selected from the group consisting of: Δ⁸-tetrahydrocannabinolic acid (Δ⁸-TCA) and Δ⁸-tetrahydrocannabinol (Δ⁸-THC).
 13. The therapeutic product of claim 1 wherein said nitric acid inducing cannabinoid compound is selected from the group consisting of: cannabiesoic acid A (CBEA-A); cannabiesoic acid B (CBEA-B) and cannabielsoin (CBE).
 14. The therapeutic product of claim 1 wherein said nitric acid inducing cannabinoid compound is selected from the group consisting of: cannabinolic acid (CBNA); cannabinol (CBN); cannabinol methylether (CBNM); cannabinol-C4 (CBN-C4); cannabivarin (CBV); cannabinol-C2 (CBN-C2); cannabiorcol (CBN-C1); cannabinodiol (CBND) and cannabidivarin (CBDV).
 15. The therapeutic product of claim 1 wherein said nitric acid inducing cannabinoid compound is selected from the group consisting of: cannabitriol (CBT); 10-Ethoxy-9-hydroxy-Δ-6a-tetrahydrocannabinol (10-EHDT); 8,9-dihydroxy-delta-6a-tetrahydrocannabinol (8,9-DHDT); cannabitriolvarin (CBTV) and ethoxy-cannabitriolvarin (CBTVE).
 16. The therapeutic product of claim 1 wherein said nitric acid inducing cannabinoid compound is selected from the group consisting of: dehydrocannabifuran (DCBF); cannabifuran (CBF); cannabichromanon (CBCN); cannabicitran (CBT); 10-oxo-Δ-6a-tetrahydrocannabinol (OTHC); Δ⁹-cis-tetrahydrocannabinol (cis-THC); 3,4,5,6-tetrahydro-7-hydroxy-α-α-2-trimethyl-9-n-propyl-2,6-methano-2H-1-benzoxocin-5-methanol (2H-iso-HHCV); cannabiripsol (CBR) and trihydroxy-Δ⁹-tetrahydrocannabinol (triOH-THC).
 17. The therapeutic product of claim 1 wherein said nitric acid inducing cannabinoid compound is selected from the group consisting of: abinene, α-pinene, 4,8-dimethyl-1,7-nonadien-4-ol, 2-hydroxy-4-methyl-valeric, acid methyl ester, octanal, O-cymene, eucalyptol, α-phellandrene, cis-sabinene, hydroxide, myrcenol, terpinen-4-ol, α-terpineol, β-thujene, ç-terpinene, trans-α-ocimene, carveol, 2-arachidonoyl-glycerol, β-citral, guanidine, geraniol, bornyl, acetate, β-pinene, thymol, geranic, acid methyl ester, α-terpinyl acetate, d-limonene, eugenol, geranyl acetate, dihydrocarvyl acetate, α-ylangene, cis-dodec-5-enal, 3-phenyl-2-propenoic, acid methyl ester, β-elemene, c, vanillin, epoxy-α-terpenyl acetate, butanoic, acid 2-methyl-, 3,7-dimethyl-2,6-octadienyl ester, 1-methyl-4-(1-acetoxy-1-methylethyl)-cyclohex-2-enol, 1,2,3,4,4a,5,6,8a-octahydro-4a,8-dimethyl-2-(1-methylethenyl)-, [2r-(2à,4aà,8aá)]-naphthalene, p-mentha-1(7),8-dien-2-ol, ç-muurolene hydroxy-α-terpenyl acetate, nerolidol, geranyl bromide, (−)-α-panasinsene, pyrocatechol, ç-elemene, 9,10-dehydro-isolongifolene, à-calacorene, cis-verbenol acetic, acid, 1-methyl-1-(4-methyl-5-oxo-cyclohex-3-enyl)ethyl ester, alloaromadendrene, z,z-2,6-dimethyl-3,5,7-octatriene-2-ol, 4-epi-cubedol, 2-oxabicyclo[2.2.2]octan-6-ol, 1,3,3-trimethyl-acetate, patchoulane, farnesol, caryophyllene oxide, cis-lanceol, ledene oxide-(ii), farnesol acetate, 6-epi-shyobunol, falcarinol, phytol, aromadendrene oxide-(2), heptacosane, longipinene, epoxide, hentriacontane, decamethyl-cyclopentasiloxane, geranyl, isobutyl, hexamethyl-cyclotrisiloxane, 1-docosene, tetratetracontane, dodecamethyl-cyclohexasiloxane, methanandamide, LY-320135, 0-1184, CP-272871, URB447, SR141716A, WIN 55,212-2, ACEA, JWH 133, GP1a, AZD 1940 and AZD
 1704. 18. The therapeutic product of claim 1 wherein said nitric acid inducing cannabinoid compound comprises a CB₁ agonist.
 19. The therapeutic product of claim 1 wherein said nitric acid inducing cannabinoid compound comprises a CB₂ agonist.
 20. The therapeutic product of claim 1 wherein said nitric acid inducing cannabinoid compound comprises a TRPV₁ agonist.
 21. The therapeutic product of claim 1 further comprising a compound selected from the group consisting of: L-arginine and L-citrulline.
 22. The therapeutic product of claim 1 wherein ii) comprises a compound that reduces PGD₂ binding to GPR₄₄.
 23. The therapeutic product of claim 1 wherein said nitric acid inducing cannabinoid active compound comprises a substance inhibiting at least one cannabinoid metabolizing enzyme.
 24. The therapeutic product of claim 23 wherein said metabolizing enzyme is selected from the group consisting of: FAAH and MAGL.
 25. The therapeutic product of claim 1 comprising a compound A that decreases PGD₂ synthesis wherein said compound A increases activity of an arachidonate depleting pathway which does not synthesize PGD₂.
 26. The therapeutic product of claim 25 wherein said arachidonate depleting pathway is selected from the group consisting of enzymes systems or pathways resulting in the synthesis of: PGE₂, PGI₂, PGF₂, PGI₂, PGF₁α, PGF₂α and thromboxanes.
 27. The therapeutic product of claim 18 wherein ii) is selected from the group consisting of: a 5-α reductase inhibitor, a PGD₂ activity inhibitor, and an androgen receptor blocking compound in active or pro-active form.
 28. The therapeutic product of claim 27 comprising: a COX1 inhibitor.
 29. The therapeutic product of claim 28 wherein said COX1 inhibitor is selected from the group consisting of: valeryl salicylate, Cox-1 Inhibitor II, FR122047 hydrate, resveratrol and SC
 560. 30. The therapeutic product of claim 27 comprising a PGD₂ activity inhibitor.
 31. The therapeutic product of claim 29 wherein said COX1 inhibitor comprises resveratrol.
 32. The therapeutic product of claim 30 wherein said PGD₂ activity inhibitor comprises luteolin.
 33. The therapeutic product of claim 1 wherein ii) comprise a 5-α reductase inhibitor selected from the group consisting of: finasteride and dutasteride.
 34. The therapeutic product of claim 1 in a delivery format selected from the group consisting of: topical gel, mist, cream, low viscosity liquid, ointment spray, dermal patch, shampoo and conditioner.
 35. A method whereby the therapeutic product of claim 1 is delivered to a human scalp whose hair retention is desired, said method comprising: locating a telogenic or anagenic follicle on said human scalp; delivering said therapeutic product to said located follicle. 